Background and Aims: BH4 is successfully used in the clinic for inherited BH4 deficiency and BH4-responsive phenylketonuria. In recent years, BH4 supplementation has also drawn attention as a therapy for various nitric oxide synthase (NOS)-related cardiovascular pathologies. By genetic intervention, we have been able to increase cardiac intracellular BH4 levels, modify cardiac metabolism and prevent heart dysfunction in a murine model of diabetic cardiomyopathy. The aim of this study was to assess the efficacy of an oral BH4 preparation in our animal model before translating the treatment into diabetic patients. In particular, we tested whether BH4 oral supplementation would be sufficient to increase BH4/NO levels in cardiac tissue and if this would protect the diabetic heart.
Results and Methods: Diabetes was induced by streptozotocin injections over 5 consecutive days in WT mice. After 12 weeks of diabetes, mice were fed with either placebo or BH4 diet (200 mg/kg/day) for an additional 6 weeks. At the end of this period, the group of diabetic mice treated with BH4 showed a significant increase of this biopterin in the heart (9.4 ± 1.3 pmol/mg protein vs 5.8 ± 0.8 pmol/mg in non-supplemented WT. P=0.034. N=8 hearts per group), as well as an increase in the activity of NOS (0.6 ± 0.11 vs 0.2 ± 0.05 % citrulline conversion. P=0.009).
WT diabetic mice showed impaired diastolic function as indicated by tissue Doppler analysis (Lower E’/A’ ratio, P<0.001 and a higher E/E’ ratio, P<0.01. N=16 mice per group), as well as a reduction in the ejection fraction (P<0.01) independent of any decrease in NO or BH4 bioavailability. In contrast, diabetic treated with BH4 displayed preserved cardiac function. Similarly, isolated cardiomyocytes from BH4-fed diabetic mice showed preserved time to 50% relaxation and decay of intracellular calcium transients (n=53–71 cells from 5–6 hearts per group) indicating that the cardioprotective effect exerted by BH4 was intrinsic to the myocardium.
Conclusion Oral BH4 was sufficient to increase the level of this biopterin and NO availability in cardiac tissue. As a result, cardiac function was preserved in a mouse model of diabetic cardiomyopathy. These results have prompted us to test the effects of BH4 on cardiac metabolism and function in diabetic patients.
Conflict of interest None
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